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Quality of life after laparoscopic bilateraladrenalectomy for Cushing’s disease Mary T. Hawn, MD, David Cook, MD, Clifford Deveney, MD, and Brett C. Sheppard, MD, Portland, Ore
Background. Bilateral adrenalectomy to control symptoms of Cushing’s disease after failed trans-
sphenoidal operation is effective. We examined surgical outcomes and quality of life after laparoscopic
bilateral adrenalectomy for the treatment of Cushing’s disease.
Methods. Eighteen patients underwent laparoscopic bilateral adrenalectomy from November 1994
through December 2000. Patient data were obtained from chart reviews. Patients completed a follow-up
survey including the SF-36 health survey (QualityMetric Inc, Lincoln, Neb).
Results. Laparoscopic bilateral adrenalectomy was accomplished in all 18 patients. There was 1 intraop-
erative complication of a colotomy, and 2 postoperative complications including 1 pancreatic pseudocyst
and 1 hemorrhage. Three patients died at 12, 19, and 50 months after operation. At a median follow-
up of 29 months, patients reported improvement in all Cushing’s-related symptoms. Nine of 11 patients
who responded to the survey stated their heath was improved after adrenalectomy. Results of the SF-36
health survey showed significantly lower scores in all 8 measured parameters when compared with the
general population.
Conclusions: Results of laparoscopic bilateral adrenalectomy show this procedure is comparable with
open adrenalectomy in controlling symptoms of Cushing’s disease. Despite patient reported improvement
in health after adrenalectomy, this patient population continues to experience poor health as measured by
the SF-36 when compared with the general population. (Surgery 2002;132:1064-9.)
From the Departments of Surgery and Internal Medicine, Oregon Health and Science University, Portland, Ore CUSHING’S DISEASE IS both a physically and emo- the open procedure.1 The objective of this study was tionally disabling disease. The sequelae of unop- to examine the effectiveness of laparoscopic bilater- posed hypercortisolism include obesity, diabetes, al adrenalectomy on reversing the sequelae of hyper- hypertension, proximal muscle weakness, emo- cortisolism with an emphasis on patients’ quality of tional lability, and hypogonadism. The mainstay of life after adrenalectomy for Cushing’s disease.
treatment for Cushing’s disease is transsphenoidalmicro-operation of the pituitary adenoma. PATIENTS AND METHODS
A significant subset of patients fails transsphe- A retrospective review of consecutive patients noidal operation secondary to a pituitary macroade- who underwent laparoscopic bilateral adrenalecto- noma or hyperplasia. For these patients, treatment my for Cushing’s syndrome between November options consist of repeated transsphenoidal opera- 1994 and December 2000 at Oregon Health and tion, medical therapy with adrenolytic agents, radia- Science University was performed. The medical tion therapy to the pituitary gland, or bilateral records were reviewed to assess patient demograph- ics, operative parameters, and postoperative events.
Adrenalectomy has been proven effective in Follow-up consisted of a questionnaire regarding reversing the effects of hypercortisolism in patients the resolution of their sequelae from Cushing’s syn- with persistent Cushing’s disease after transphe- drome, number and frequency of addisonian noidal micro-operation. Laparoscopic adrenalecto- episodes, current corticosteroid replacement, and my can be safely performed with less morbidity than the development of Nelson’s syndrome. Patientswere asked to rate the success of their operation inimproving their health status. The SF-36 health sur- Presented at the 23rd Annual Meeting of the American vey (QualityMetric Inc, Lincoln, Neb) was also Association of Endocrine Surgeons, Banff, Alberta, Canada,April 7-9, 2002.
administered with the follow-up questionnaire toevaluate objectively their overall health status.
Reprint requests: Mary T. Hawn, MD, University of Alabama atBirmingham, KB 417, 1530 3rd Ave S, Birmingham, AL 35294- Results from the SF-36 health survey were com- pared with published normative values for the US 2002, Mosby, Inc. All rights reserved.
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Surgical technique. The procedure was per-
formed with the patient in the lateral decubitus Table I. Patient demographics and disease charac-
Table II. Response of Cushing’s disease sequelae
*Three patients were either postmenopausal or male.
position. Three to 4 trocars were used for the leftside and 4 to 5 for the right side. Patients wererepositioned between sides. Dissection was per- patient between sides, which added approximately formed primarily with the harmonic scalpel with 35 minutes on the basis of data available. The mean the exception of clips being placed on the right estimated blood loss for bilateral adrenalectomies adrenal vein. Glands were removed in an endo- was 218 mL (10-500 mL). There was 1 intraopera- scopically placed bag and the retroperitoneal beds tive complication of a colotomy secondary to adhe- were examined for completeness of gland removal. sions from a previous appendectomy that was Hydrocortisone replacement was started intraop- repaired through a limited open incision after eratively at the completion of the adrenalectomy.
completion of the adrenalectomy. There were 2 Patients were converted to oral hydrocortisone ther- postoperative complications, 1 postoperative hem- apy once they were tolerating a clear liquid diet, orrhage that was managed laparoscopically and and discharged when tolerating a regular diet and resulted in a 1-U transfusion. The second compli- cation of postoperative pancreatitis resulted in Six patients underwent confirmation of complete- pseudocyst formation that has been managed con- ness of adrenalectomy. Postoperatively they were servatively. The median duration of stay was 3 days placed on dexamethasone replacement therapy and (range, 1-18 days). The patient who had the 18-day a serum cortisol level was measured the next morn- hospital stay was severely debilitated and had sig- ing. Undetectable serum cortisol levels confirmed nificant mental status changes secondary to her absence of adrenal tissue. They were subsequently Cushing’s disease. She ultimately was discharged to converted to standard hydrocortisone therapy before a nursing home. Otherwise, all patients were dis- The mean combined adrenal weight was 30 g and ranged from 11 to 62 g with normal combined Eighteen patients underwent laparoscopic bilat- weight being 4 to 12 g. Documentation of com- eral adrenalectomy for Cushing’s syndrome during pleteness of adrenalectomy after the laparoscopic the study period. Demographic variables, duration procedure was done in the initial 6 patients of this of disease, and number of previous interventions are series. Dexamethasone was given for postoperative outlined in Table I. All patients had documented steroid replacement and serum cortisol was mea- Cushing’s syndrome and increased 24-hour urinary sured on postoperative day 1. All 6 patients had free cortisol levels, mean 152 µg/dL (range, 47- undetectable serum levels of cortisol confirming 366). Sixteen patients underwent transsphenoidal complete removal of both adrenal glands.
micro-operation at a median of 6.5 months (1-240 The median follow-up was 29 months. Three months) before adrenalectomy. One of the patients patients died at 12, 19, and 50 months after adrena- who underwent transsphenoidal operation was later lectomy from a cardiac event, stroke, and pneumo- diagnosed with bilateral adrenal dependent disease.
nia, respectively. The age of these patients at death Five patients underwent a second transsphenoidal was 69, 73, and 74 years. Of the 15 patients available micro-operation at a median of 18 months (3-29 for follow-up, 14 were contacted by telephone to months) before adrenalectomy. One patient who confirm their address and 11 returned the survey, failed 2 transsphenoidal procedures also received γ- for a 73% response rate. The effectiveness of adrena- knife treatment 27 months before adrenalectomy. lectomy in reversing the sequelae of Cushing’s dis- ease is shown in Table II. Hypertension, diabetes, accomplished in all patients with a mean operative and depression were defined by the requirement of time of 296 minutes (160-420 minutes). The oper- medication for treatment of the disorder. The ative time includes repositioning and prepping the patients had a mean weight loss of 8 kg (3-19kg). Table III. Results of SF-36 survey in patients after adrenalectomy compared with the general population
*Norms from the general US population published in SF-36 health survey manual.2 All patients were discharged on hydrocortisone mas and falls to 65% for macroadenomas and 38% 15 mg twice a day and fludrocortisone acetate 0.1 to 43% for recurrent or persistent disease.3-6 The mg/day. Between 6 and 18 months after operation, treatment of patients who fail transsphenoidal there was a decrease in the steroid replacement micro-operation for the treatment of Cushing’s dis- therapy to approximately 15 to 20 mg per day in ease is a challenging clinical problem. Options divided doses. Seven of the 11 patients (64%) include medical adrenalytic therapy, repeated report seeking emergency care for steroid replace- transsphenoidal operation, γ-knife irradiation, and ment at least once. Most of these events occurred during the first year after adrenalectomy and were Medical therapy is often poorly tolerated as a related to vomiting and inability to take steroid result of the side effects of chronic therapy. γ-Knife irradiation to the pituitary gland for the treatment Ten of the 11 patients who responded to the of Cushing’s disease is effective in 63% to 83% of questionnaire had pituitary dependent Cushing’s patients depending on the duration of follow-up.7-9 disease. One patient had Nelson’s syndrome devel- However, most patients don’t achieve normal corti- op 36 months after adrenalectomy and was treated sol levels until 6 to 18 months after treatment.
with γ-knife irradiation. Six patients (60%) had dis- Furthermore, the incidence of pituitary deficiencies turbance in at least 1 other pituitary axis requiring in other axes after γ-knife therapy ranges from 17% treatment. Five had growth hormone deficiency, 2 had gonadal insufficiency, and 1 had permanent Bilateral adrenalectomy is effective in reversing the signs and symptoms of Cushing’s disease.10-12 Four of the 11 patients are currently employed The introduction of the laparoscopic approach to and returned to work between 1 and 5 months adrenalectomy has decreased the operative morbid- after adrenalectomy. Of the 7 who are not working, ity of this procedure and several reports have con- 3 stated that their current health status was pre- firmed that it is a feasible approach for patients with venting them from doing so. Nine patients (82%) Cushing’s disease.13-16 Adrenalectomy renders state that their health is improved after adrenalec- patients dependent on steroid replacement therapy tomy; 1, unchanged; and 1, worse. Results of the for the remainder of their lives. Previous reports SF-36 health survey are displayed in Table III.
have found that 9% to 20% of patients needed Scores are transformed to a 0 to 100 scale with 100 treatment for Addisonian episodes after adrenalec- representing the best perceived health. The 8 tomy.10,17 We found that 63% of our patients sought health concepts cover physical and emotional emergency care for steroid deficiency. These are health, vitality, and perceived pain. Scores on all 8 self-reported episodes and were not confirmed by parameters of the health survey are significantly obtaining medical records. Most patients stated that lower than published normative scores for the gen- they sought care secondary to vomiting and inabili- ty to take their steroid replacement orally. Bilateral adrenalectomy for pituitary dependent DISCUSSION
Cushing’s disease places the patient at risk for devel- Transsphenoidal micro-operation is the treat- oping Nelson’s syndrome. The incidence of ment of choice for patients with Cushing’s disease.
Nelson’s syndrome after adrenalectomy ranges The success rate is 90% for pituitary microadeno- from 15% to 30% depending on the duration of fol- low-up.10,11,17,18 Prior pituitary irradiation is protec- 15 patients were less than age 65 years (18-63). Of tive against the development of Nelson’s syndrome, interest is that all 3 patients who died had poorly factors that are associated with the development of controlled hypertension before definitive treat- the syndrome are subnormal or noncontinuous ment of their Cushing’s disease, despite being on 2 steroid replacement, female gender, pretreatment to 4 medications, whereas only 4 of the remaining urinary cortisol level, and presence of a pituitary 15 patients were on 2 or more medications.
adenoma.10,18 One patient in our series had This report confirms that laparoscopic bilateral Nelson’s syndrome develop 35 months after adrena- adrenalectomy is effective in controlling the compli- lectomy; however, our follow-up is relatively short. cations of Cushing’s disease. Patients enjoy improve- Although 81% of our patients who responded to ment in their health status after definitive treatment this survey stated that their health was improved of their disease; however, most continue to have after adrenalectomy, they scored substantially lower poorer health than the general population. The sus- on the SF-36 health survey when compared with tained effects of Cushing’s disease appear to be the general population. The SF-36 is a generic more related to the disease process rather than the health status survey that is not age-, disease-, or treatment imposed. We recommend laparoscopic treatment-specific. It has been well-validated in bilateral adrenalectomy as the preferred treatment measuring health status in multiple chronic dis- in patients who fail transsphenoidal pituitary opera- eases and the general population.2 The low scores tion. Adrenalectomy predictably and immediately in our patient population did not correlate with reverses the hypercortisolic state in Cushing’s dis- duration of follow-up, duration of disease before ease. Because of the frequent disturbances in other adrenalectomy, or preoperative urinary cortisol lev- pituitary axes, we reserve γ-knife radiation for those els. We did not collect preoperative SF-36 data on who have signs of developing Nelson’s syndrome.
our patients, and so we cannot measure specificchanges in their health after adrenalectomy. We REFERENCES
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2. Ware JE Jr, Snow KK, Kosinski M. SF-36 health survey: man- Other investigators have also found that patients ual and interpretation guide. Lincoln (RI): Qualitymetric with cured Cushing’s disease demonstrate marked impairment in both physical and mental health 3. Swearingen B, Biller BM, Barker FG, Katznelson L, scores as measured by the SF-36.10,19 Persistent Grinspoon S, Klibanski A, et al. Long-term mortality after poor health after definitive treatment of Cushing’s transsphenoidal surgery for Cushing disease. Ann InternMed 1999;130:821-4.
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worse when patients failed initial pituitary opera- Transsphenoidal pituitary surgery in Cushing’s disease: can tion. The explanation for these findings seem to be we predict outcome? Clin Endocrinol (Oxf) 2001;54: more related to the long-standing sequelae of 7. Estrada J, Boronat M, Mielgo M, Magallon R, Millan I, Diez hypercortisolism rather than the treatment S, et al. The long-term outcome of pituitary irradiation after imposed. Our study does not define the reason for unsuccessful transsphenoidal surgery in Cushing’s disease.
continued perception of poor health.
The natural history of untreated Cushing’s dis- 8. Sheehan JM, Vance ML, Sheehan JP, Ellegala DB, Laws ER.
ease is poorly documented, but 1 study from 1952 Radiosurgery for Cushing’s disease after failed transsphe-noidal surgery. J Neurosurg 2000;93:738-42.
reported a 5-year mortality rate that was greater 9. Clarke SD, Woo SY, Butler EB, Dennis WS, Lu H, Carpenter than 50%.20 Consistent with this, survival in LS, et al. Treatment of secretory pituitary adenoma with patients with Cushing’s disease is much poorer for radiation therapy. Radiology 1993;188:759-63.
those patients who fail initial treatment with trans- 10. Nagesser SK, vanSeters AP, Kievit J, Hermans J, Krans HM, sphenoidal operation.19 During our follow-up peri- van de Velde CJ. Long-term results of total adrenalectomyfor Cushing’s disease. World J Surg 2000;24:108-13.
od, 3 of the 18 patients died from causes unrelated 11. Chapuis Y, Pitre J, Conti F, Abboud B, Pras-Jude N, Luton to operation. All 3 patients were more than age 65 JP. Role and operative risk of bilateral adrenalectomy in years at the time of adrenalectomy, the remaining hypercortisolism. World J Surg 1996;20:775-9.
12. Zeiger MA, Fraker DL, Pass HI, Nieman LK, Cutler GB, Dr Hawn. Approximately 8 of these patients contin-
Chrousos GP, et al. Effective reversibility of the signs and ued to be followed-up at Oregon Health and Sciences symptoms of hypercortisolism by bilateral adrenalectomy.
University, by our study endocrinologist. To my knowl- edge, none of them have had long-term biochemical fol- 13. Vella A, Thompson GB, Grant CS, vanHeerden JA, Farley low-up. But I agree that would be a nice addition to this DR, Young WF Jr. Laparoscopic adrenalectomy for adreno- study to confirm completeness of the adrenalectomy.
corticotropin-dependent Cushing’s syndrome. J Clin Dr Laurant Brunaud (San Francisco, California). My
14. Lanzi R, Montorsi F, Losa M, Centemero A, Manzoni MF, question is more related to the methodology you used.
Rigatti P, et al. Laparoscopic bilateral adrenalectomy for In your opinion, is an SF-36 questionnaire adequate or persistent Cushing’s disease after transsphenoidal surgery.
very accurate regarding the patient after laparoscopic adrenalectomy, especially when you have symptoms? Do 15. Acosta E, Pantoja JP, Famino R, Rull JA, Herrera MF.
you think that more specific tools than the ones you use Laparoscopic versus open adrenalectomy in Cushing’s syn- are mandatory and better? And does this specific ques- drome and disease. Surgery 1999;126:1111-6.
16. Bax TW, Marcus DR, Galloway GO, Swanstrom LL, Dr Hawn. The specific questionnaire that I used with
Sheppard BC. Laparoscopic bilateral adrenalectomy follow- regards to Cushing’s syndrome is not validated and was ing failed hypophysectomy. Surg Endosc 1996;10:1150-3. really trying to get at the resolution of the sequelae of 17. O’Riordain DS, Farley DR, Young WF Jr, Grant CS, van Heerden JA. Long-term outcome of bilateral adrenalecto- Cushing’s disease. I think the 2 questionnaires are com- my in patients with Cushing’s syndrome. Surgery 1994; plementary. The SF-36 is well-validated in multiple chronic disease processes. Because this patient popula- 18. Sonino N, Zielezny M, Fava GA, Fallo F, Boscaro M. Risk fac- tion is small, I think it will be challenging to get a well- tors and long-term outcome in pituitary-dependent validated, specific questionnaire for them.
Cushing’s disease. J Clin Endocrinol Metab 1996;81:2647-52.
The thing that I think is useful about the SF-36 is it 19. Lindholm J, Juul S, Jorgensen JOL, Astrup J, Bjerre P, Feldt- addresses both physical and mental health, which are Rasmussen U, et al. Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin But I think a complementary disease-specific ques- tionnaire is helpful to show that we do improve the symp- 20. Plotz CM, Knowlton AI, Ragan C. The natural history of Cushing’s syndrome. Am J Med 1952;13:597-614.
toms related to Cushing’s despite the prolonged effectthe disease has on patient health.
Dr William B. Inabnet, III (New York, New York). I
DISCUSSION
agree 100% with your conclusions. When patients have Dr Quan-Yang Duh (San Francisco, California). I want
failed pituitary-directed treatment for Cushing’s disease, to say that I completely agree with you in terms of the they are given medical therapy and experience severe recommendation that this is a treatment of choice for a progression disease. When these patients are ultimately patient who has a failed operation. You did state in your referred for adrenalectomy as a result of failure of final conclusion that this may be a primary treatment for medical therapy, they have multiple comorbidities from pituitary-dependent, adrenocorticotropic hormone- cortisol excess, which increases the perioperative com- dependent Cushing’s syndrome. Did I catch that cor- In the 4 patients who had complications in your Dr Hawn. If I said that, then I misspoke.
series, what was the interval from the failed pituitary Adrenalectomy should be primary treatment for patients treatment to adrenalectomy and did those patients who have failed transphenoidal pituitary operation. And undergo medical therapy? Was there a higher complica- often the patients who have failed are patients with a very tion rate in patients who received medical therapy? aggressive pituitary tumor, such as a macroadenoma. We Dr Hawn. I don’t believe that any of the patients in
recommend that they go on to adrenalectomy rather our study underwent a prolonged attempt at medical than a repeated transphenoidal procedure, and we rec- therapy. The endocrinologist who we work with confirms ommend reserving the γ-knife for patients in whom signs the diagnosis quickly and refers them for operation. The or symptoms of Nelson’s syndrome develop.
median time between transphenoidal operation and Dr L. Michael Brunt (St. Louis Missouri). My ques-
adrenalectomy was 6 months in our study population.
tion relates to the biochemic follow-up. There have And to my knowledge (and I would have to look at the been some casess reported which, with biochemical data more carefully) the duration of the disease did not testing and adrenocorticotropic hormone stimulation, there is evidence of some residual cortical function Dr Inabnet. I think your conclusion of early surgical
after bilateral adrenalectomy for patients who have intervention is warranted and well-supported by your been treated laparoscopically. I was just wondering if you have any long-term biochemic follow-up on these Dr Janice L. Pasieka (Calgary, Alberta, Canada). Were
patients and if you carried out adrenocorticotropic hor- all of your patients on the same dose of prednisone and mone stimulation testing in any of these patients or have you done 24-hour urine cortisols during long-term Dr Hawn. Yes, all patients were discharged on 30 mg
of hydrocortisone in divided doses and 0.1 mg of Florinef. Most patients were then weaned to some- actually continue to improve these patients’ lives after where between 15 to 20 mg of hydrocortisone in divid- ed doses within about 5 months after adrenalectomy.
Dr Hawn. One of the things that we have found is
Dr Thomas J. Fahey, III (New York, New York). Your
because patients have had multiple previous transphe- data is excellent, and I think it confirms what many of noidal procedures, they often had disturbances in other us have seen in patients who have had bilateral adrena- pituitary axises. And I think aggressive diagnosis and lectomy. I am wondering if you or your endocrinolo- management of those axises has helped in improving gist have made any proposals or adjustments in how to

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